Tuberculosis (TB) case rates have continued to increase globally. Lack of an efficient vaccine and non- compliance to prolonged treatment have contributed to continued transmission of this infectious agent and to the rise of multidrug-resistant TB. With the aid of a previous NIH R21 grant, we have identified a gene and a pathway conferring increased susceptibility to TB. Our short term goal is to better understand how this gene confers susceptibility to development of active TB. Our long-term goal is to translate this knowledge into new clinical interventions, and public health strategies to control the spread of TB. Our aims are: Specific Aim 1: To confirm in a second population the association of the MCP-1 allele G and genotypes AG and GG with susceptibility to developing TB. We have carefully designed these studies to exclude co-morbidities affecting immunity and to ensure correct ascertainment of the phenotypes of primary TB, healthy tuberculin reactors and healthy tuberculin-negative persons. Specific Aim 2: To determine if the - 1607 MMP-1 functional polymorphism has a significant main effect and/or interacts with the MCP-1 allele G to modify the expression of susceptibility to developing active pulmonary TB. We seek to confirm that the MMP- 1 genotypes 1G/2G and 2G/2G are associated with development of primary pulmonary TB, and determine if these MMP-1 genotypes interact with the MCP-1 allele G to increase the odds of developing active TB. Specific Aim 3: To investigate the mechanisms by which the MMP-1 and MCP-1 polymorphisms may interact to enhance susceptibility to development of primary pulmonary TB. We will investigate whether the presence of functional polymorphisms in MMP-1 in TB cases carrying the MCP-1 allele G modify the expression of MCP-1, MMP-1, IL-12p40, and IL-12p70in plasma and PBMC. We will infect in vitro with M. tuberculosis the monocytes of healthy donors who are carriers of the most prevalent and biologically relevant combinations of MCP-1 and MMP-1 genotypes, and study the interactions of MMP-1 and MCP-1, using recombinant proteins, neutralizing antibodies and siRNA. Using these monocytes infected in vitro, we will determine if increased availability of MCP-1 and MMP-1 facilitate MMP-1 processing of MCP-1 to produce 5-76 MCP-1 truncated peptides that inhibit production of IL-12p40 and IL-12p70, key components in the development of effective immunity against M. tuberculosis.